Pathological hallmarks of Alzheimer's disease (AD) include extracellular deposits of A? peptides, intraneuronal aggregates of abnormally phosphorylated tau protein and neuroinflammation. Most proposed AD disease modifying therapies have focused on strategies that reduce brain A?/amyloid or tau pathological accumulation. However, such approaches have been unsuccessful in late stage AD clinical trials and may only be most useful as prophylactics, leaving millions of AD patients without therapeutic options. There is therefore a critical need to evaluate therapeutic targets downstream of A?/amyloid and tau pathologies. We have determined that the spleen tyrosine kinase (SYK) is pathologically activated in neurons and microglia both in AD patients and in AD preclinical mouse models, and colocalizes with AD pathological hallmarks, suggesting SYK is a downstream target of A? and tau pathologies. We have identified that nilvadipine, a known antihypertensive dihydropyridine (DHP), that improves cognition and reduces the development of AD pathological hallmarks including neuroinflammation in AD preclinical models, mediates its AD effects via an allosteric inhibition of SYK highlighting SYK as a therapeutic target for AD. We have recently concluded a large randomized, double- blind, placebo-controlled phase III trial of nilvadipine in mild to moderate AD revealing that nilvadipine has cognitive benefits for mild, particularly very mild, AD in whom it slows the rate of cognitive decline. The main goal of these studies is the development of a selective SYK negative allosteric modulator (NAM), more potent than nilvadipine, for the treatment of AD without the blood pressure lowering effects. As the orthosteric site configuration is conserved among kinases, which can lead to a lower specificity of a drug, resulting in adverse side effects, we elected a drug discovery strategy exploiting SYK allosteric sites to lead to more selective therapeutic agents. In this Fast Track STTR application, Phase I will allow the identification of a suitable SYK NAM scaffold for drug development and the establishment of computational models to orient the rational design and synthesis of novel SYK NAMs. Phase II will improve the SYK inhibitory activity and optimize the ADME (Absorption, Distribution, Metabolism, and Excretion) properties of the SYK NAM scaffolds to identify an advanced SYK NAM scaffold lead. The efficacy of the lead SYK NAM will be ultimately explored in preclinical models of AD exhibiting A?, tau and inflammatory pathologies. Given our previous preclinical data obtained with nilvadipine and another selective SYK inhibitor (BAY61-3606), we anticipate that targeting SYK with a SYK NAM should alleviate some of the downstream consequences of A? and tau accumulation including neuroinflammation, synaptic loss and neurodegeneration, and should also reduce the propagation of the tau pathology and A?/amyloid accumulation. The SYK NAM scaffolds that we are developing have the potential to simultaneously affect neuroinflammatory processes, A?/amyloid and tau pathologies and may lead to more effective AD treatments than targeting a single pathological aspect of the disease.